The long-term objective of this proposal is to discover novel prokinetic agents with superior pharmacological and pharmacokinetic properties for the treatment of gastrointestinal motility disorders such as gastroesophogeal reflux disease (GERD), gastroparesis, postoperative ileus, scleroderma, gallstones, and as a quick and effective drug to stimulate stomach emptying in patients requiring emergency surgery. We propose to prepare the first member of a new class of acid-stable erythromycin analogs from a novel erythromycin scaffold obtained through genetic engineering of the erythromycin gene cluster. The analog will be tested for acid stability and its ability to serve as an effective pro- kinetic agent ("motilide"). A lead compound made in this fashion will serve as a scaffold for future preparations of novel acid-stable semi- synthetic motilides during Phase II of this program. PROPOSED COMMERCIAL APPLICATIONS: The ideal motilide will be a safe and effective treatment for common heartburn. Motilides are anticipated to have applications for the treatment of diabetic gastroparesis, postoperative ileus and scleroderma. The stimulatory effects of motilides on gallbladder contraction suggest that they may' find application in patients at risk of gallstone formation. Finally, intravenous administration of motilides has been recommended as a quick and safe procedure to empty the stomach before emergency surgery, and in pregnant women undergoing caesarian delivery.